Houttuynia cordata Polysaccharide Alleviates Hepatic Ischemia-Reperfusion Injury by Regulating Macrophage Polarization via Inhibiting the TLR4/NF-κB Signaling Pathway

<b>Background:</b> Hepatic ischemia-reperfusion injury (HIRI) is a major complication in liver surgery with limited therapeutic options. <i>Houttuynia cordata</i> polysaccharide (HCP), a key bioactive component of the traditional anti-inflammatory herb, has demonstrated immunomodulatory potential, but its effect on HIRI remains unclear. <b>Methods:</b> A murine model of 70% hepatic ischemia for 60 min followed by reperfusion was established. Mice were administered low-dose (50 mg/kg) or high-dose (100 mg/kg) HCP or the positive control N-acetylcysteine (150 mg/kg). Liver injury was assessed by serum ALT/AST levels, histopathology, oxidative stress markers, and inflammatory cytokines. Macrophage polarization and the TLR4/NF-κB pathway were analyzed using flow cytometry, qPCR, and Western blot. The TLR4 inhibitor TAK-242 was used for reverse validation, and molecular docking was performed to predict HCP binding to the TLR4/MD-2 complex. <b>Results:</b> HCP significantly attenuated HIRI-induced liver injury, as shown by reduced ALT/AST, improved histopathological scores, decreased MDA, increased SOD, and lower TNF-α and IL-6 levels. Mechanistically, HCP promoted a shift from M1 to M2 macrophage polarization, with increased CD206⁺ cells and Arg-1/IL-10 expression and decreased CD86⁺ cells and iNOS/IL-1β expression. HCP also suppressed TLR4/MyD88/NF-κB pathway activation, inhibiting NF-κB p65 phosphorylation and nuclear translocation. These protective effects were largely reversed by TAK-242 in vivo and in vitro. Molecular docking indicated stable binding between HCP and TLR4/MD-2. <b>Conclusions:</b> HCP protects against HIRI by targeting TLR4 to inhibit NF-κB signaling, thereby reprogramming macrophage polarization toward the M2 phenotype and alleviating inflammation and oxidative stress. These findings highlight HCP as a promising natural agent for HIRI intervention.